Premenstrual Dysphoric Disorder (PMDD)

Premenstrual dysphoric disorder (PMDD) is a severe mood disorder characterized by core symptoms such as affective lability, irritability, depressed mood, and anxiety, which occur during the luteal phase of the menstrual cycle.

PMDD can be understood as a disorder of suboptimal sensitivity to neuroactive steroid hormones (NASs) (Pearlstein 2012). One of the key NASs involved in PMDD's pathophysiology is allopregnanolone, a positive allosteric modulator of the GABAA receptor (GABAA-R)(Sun et al. 2023).

The hormone sensitivity hypothesis suggests that PMDD represents an aberrant response to sex steroid hormones, and growing evidence indicates that the primary symptoms of PMDD, such as mood lability, anxiety, and irritability, often worsened by stress, reflect suboptimal GABAA-R sensitivity to allopregnanolone (Pearlstein 2012).

 PMDD's pathophysiology likely involves altered central nervous system (CNS) sensitivity to NAS hormones, which is reflected in symptom emergence during a hormonally dynamic phase of the menstrual cycle (Pearlstein 2012).

Impaired interaction between allopregnanolone and GABAA-Rs has been observed in terms of affective symptom expression, with evidence from both rodent and human studies (Sun et al. 2023). Additionally, increased luteal phase stress sensitivity has been linked to poor allopregnanolone-GABA control of the hypothalamic-pituitary-adrenal (HPA) axis(Sun et al. 2023).

Treatments such as selective serotonin reuptake inhibitors (SSRIs) and new drugs targeting GABAA-Rs provide evidence for impaired allopregnanolone-GABA function in PMDD(Sun et al. 2023). In summary, the literature supports the hypothesis that PMDD pathophysiology is rooted in impaired GABAA-R response to dynamic allopregnanolone fluctuations across the menstrual cycle, manifesting in affective symptoms and poor regulation of the physiological stress response (Pearlstein 2012; Sun et al. 2023).

Aetiology and Risk Factors

PMDD is a severe form of premenstrual syndrome (PMS) that affects 5.8% of menstruating women. The exact aetiology of PMDD is still unclear, but it is believed to be related to hormonal changes during the menstrual cycle and their impact on neurotransmitters, particularly serotonin.

Risk factors for PMDD include a history of mood disorders, such as depression and anxiety. Additionally, women with PMDD have a higher percentage of past psychiatric disorders than women without the disorder.

• Family history of PMS or PMDD
• Personal or family history of depression, postpartum depression, or other mood disorders
• Past traumatic events and pre-existing anxiety disorders
• Cigarette smoking
• Stress
• Being overweight or obese
• Past history of trauma or sexual abuse
• Signs and Symptoms

Common symptoms of PMDD include mood swings, irritability, depression, anxiety, fatigue, difficulty concentrating, and changes in appetite and sleep patterns. These symptoms typically occur during the luteal phase of the menstrual cycle and resolve within a few days after the onset of menstruation. PMDD can significantly impact a woman's quality of life, leading to functional impairment and decreased well-being.

• Lasting irritability or anger that may affect other people
• Feelings of sadness or despair, or even thoughts of suicide
• Feelings of tension or anxiety
• Panic attacks
• Mood swings or crying often
• Lack of interest in daily activities and relationships
• Trouble concentrating
• Fatigue
• Physical problems such as breast tenderness, headaches, joint or muscle pain, and swelling or bloating
• Trouble sleeping

Diagnosis

The term PMS continues to be used to encompass a wide range of severity and therefore is not particularly useful in defining cohorts for research or in directing the most appropriate therapeutic interventions (Reid 2017).

PMDD should be reserved for a more severe constellation of symptoms, mostly psychiatric, that lead to periodic interference with day-to-day activities and interpersonal relationships. Women with this degree of symptoms probably comprise 3-5% of women in their reproductive years (Reid 2017).

Diagnosis of PMDD is based on the presence of specific symptoms during the luteal phase of the menstrual cycle, as outlined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). A thorough clinical evaluation, including a detailed history of menstrual symptoms and their impact on daily functioning, is essential for accurate diagnosis. Prospective daily symptom ratings for at least two menstrual cycles are recommended to confirm the diagnosis.

The diagnostic criteria for premenstrual dysphoric disorder (PMDD) according to the American Psychiatric Association are as follows:

A. In the majority of menstrual cycles, at least five symptoms must be present in the final week before the onset of menses, start to improve within a few days after the onset of menses, and become minimal or absent in the week post menses.

B. One (or more) of the following symptoms must be present:

1. Marked affective lability (e.g., mood swings; feeling suddenly sad or tearful, or increased sensitivity to rejection)
2. Marked irritability or anger or increased interpersonal conflicts
3. Marked depressed mood, feelings of hopelessness, or self-deprecating thoughts
4. Marked anxiety, tension, and/or feelings of being keyed up or on edge

C. One (or more) of the following symptoms must additionally be present, to reach a total of five symptoms when combined with symptoms from criterion B above:

Decreased interest in usual activities (e.g., work, school, friends, hobbies)
Subjective difficulty in concentration
Lethargy, easy fatigability, or marked lack of energy
Marked change in appetite, overeating, or specific food cravings
Hypersomnia or insomnia
A sense of being overwhelmed or out of control
Physical symptoms such as breast tenderness or swelling, joint or muscle pain, a sensation of bloating, or weight gain
Severity

D) The symptoms are associated with clinically significant distress or interference with work, school, usual social activities, or relationships with others.

E) Consider Other Psychiatric Disorders. The disturbance is not merely an exacerbation of the symptoms of another disorder, such as major depressive disorder, panic disorder, persistent depressive disorder (dysthymia) or a personality disorder (although it may co-occur with any of these disorders).

Confirmation of the disorder

F) Criterion A should be confirmed by prospective daily ratings during at least 2 symptomatic cycles (although a provisional diagnosis may be made prior to this confirmation).

Exclude other Medical Explanations

G) The symptoms are not attributable to the physiological effects of a substance (e.g., drug abuse, medication or other treatment) or another medical condition (e.g., hyperthyroidism).

Complications of Premenstrual Dysphoric Disorder

Premenstrual dysphoric disorder (PMDD) can lead to various complications in affected women. Some of the complications include:

Physical complications: Women with PMDD may experience extreme pain, tachycardia, dizziness, nausea, vomiting, decreased blood pressure, loss of appetite, sleep disorders, lack of libido, and fatigue (Almaraz Trejo and Castillo Marínez 2023).
Emotional complications: PMDD can cause irritability, crying, social withdrawal, guilt and worthlessness, anxiety, depression, suicidal ideation or intention, stress, and burnout syndrome (Almaraz Trejo and Castillo Marínez 2023).

Impact on daily life and work performance: PMDD can significantly affect a woman's daily functioning and work performance, leading to decreased productivity and increased absenteeism (Almaraz Trejo and Castillo Marínez 2023).

Sleep disturbances: Even after treatment with selective serotonin reuptake inhibitors (SSRIs), some women with PMDD may continue to experience sleep disturbances, such as hypersomnia and insomnia (Yamada and Kanba 2007).

Increased risk of other health issues: Women with PMDD may have a higher risk of developing other health problems, such as neurocirculatory dystonia, headache, and migraine (Hapsari, Mantani, and Matsuo 2006).

It is essential for women with PMDD to receive appropriate care and support to manage these complications and improve their quality of life.

Treatment

Dietary Recommendations

Dietary changes can help manage PMDD symptoms. Some recommendations include:

• Eating a diet rich in vegetables, fruits, and healthy fibre
• Reducing salt intake
• Eating a variety of fruits and vegetables, focusing on leafy greens
• Drinking plenty of water
• Eating small, frequent meals to combat bloating and stomach upset
• Choosing complex carbohydrates such as whole grains
• Antihistamines may provide relief for premenstrual mood symptoms.
• A dairy-free diet has been suggested as a potential treatment for PMS and PMDD, but more research is needed to confirm its effectiveness.

Exercise

Incorporating regular exercise, stress management techniques, and dietary modifications can help manage PMDD symptoms.

Psychotherapy

Talking therapy and counselling: Cognitive-behavioural therapy (CBT) and other forms of counselling can help manage the emotional symptoms of PMDD.

Light therapy

A study investigated the effects of bright light therapy on women with late luteal phase dysphoric disorder. The researchers conducted a six-menstrual cycle randomized, double-blind, counter-balanced, crossover study with 14 women who met the DSM-III-R criteria for late luteal phase dysphoric disorder.

The participants completed two menstrual cycles of baseline monitoring, followed by two cycles of each treatment. During the two-week luteal phase of each treatment cycle, patients were randomized to receive 30 minutes of evening light therapy using either 10000 lux cool-white, fluorescent light (active condition) or 500 lux red fluorescent light (placebo condition) through a light box at their homes.

After two menstrual cycles of treatment, patients were immediately crossed over to the other condition for another two cycles. Outcome measures were assessed at the mid-follicular and luteal phases of each cycle.

The results showed that the active bright white light condition significantly reduced depression and pre-menstrual tension scores during the symptomatic luteal phase compared to baseline, while the placebo dim red light condition did not. These findings suggest that bright light therapy is an effective treatment for late luteal phase dysphoric disorder (Lam et al. 1999).

Pharmaceuticals
Selective serotonin reuptake inhibitors (SSRIs)

These antidepressants, such as sertraline (Zoloft), citalopram (Celexa), and fluoxetine (Prozac), is considered the first-line treatment for PMDD (Pearlstein and Steiner 2008; Lovick 2013).

Selective serotonin reuptake inhibitors (SSRIs) exhibit unique properties when used for premenstrual dysphoric disorder (PMDD) treatment, such as rapid therapeutic effects and efficacy at low doses. In women with PMDD, SSRIs typically reduce symptoms within one to three days, which is faster than the weeks often required for response to SSRIs in major depression (Steiner and Li 2013).

Using hourly mood ratings, nearly two-thirds of women with PMDD experienced a 50% reduction in symptoms relative to baseline within two days of luteal phase fluoxetine treatment. Placebo-controlled trials also showed that luteal phase administration of sertraline and paroxetine were more effective than placebo in reducing PMDD symptoms (Steiner and Li 2013). SSRIs are effective at low doses in PMDD, for instance, 25–50 mg sertraline or 20 mg fluoxetine (Steiner and Li 2013).

These unique characteristics of SSRIs in PMDD treatment suggest that the therapeutic effect is not entirely serotonergic. One suggested mechanism is that SSRIs alter the conversion of progesterone to allopregnanolone.

According to this hypothesis, SSRIs increase the conversion of the progesterone metabolite 5α-dihydroprogesterone (5α-DHP) to allopregnanolone, via SSRI action on enzymes that catalyse this conversion. In this case, the SSRI would be acting as a selective brain steroidogenic stimulant (SBSS) (Griffin and Mellon 1999).

Research in animals suggests that SSRIs enhance allopregnanolone biosynthesis. Clinically, an open-label trial of sertraline in women with severe PMS or PMDD found that the SSRI increased peripheral allopregnanolone levels in women with low baseline allopregnanolone and decreased allopregnanolone in women with high baseline levels (Griffin and Mellon 1999).

• Combined oral contraceptives
• Birth control pills containing both estrogen and progestin can help regulate hormone levels and alleviate PMDD symptoms, although it should be pointed out that PMDD is not regarded as a disorder of oestrogen excess.
• Painkillers or anti-inflammatory drugs
• Over-the-counter pain relievers, such as ibuprofen or naproxen, can help alleviate physical symptoms like cramps, headaches, and muscle pain.
• Gonadotropin-releasing hormone (GnRH) analogue injections
• These injections can suppress ovarian function and reduce PMDD symptoms, but they are typically reserved for severe cases that do not respond to other treatments.

GABA-modulating drugs

Research over the past two decades has suggested that the interaction between allopregnanolone, a neurosteroid derivative of progesterone, and the gamma-aminobutyric acid (GABA) system represents an important relationship underlying symptom genesis in reproductive-related mood disorders, including premenstrual dysphoric disorder (PMDD).

A narrative review discussing the plausible link between changes in GABAergic transmission secondary to the fluctuation of allopregnanolone during the luteal phase and mood impairment in susceptible individuals was published recently (Sikes-Keilp and Rubinow 2023).

Promising Findings from Early Clinical Trials

As part of this discussion, the review explores promising findings from early clinical trials of several compounds that stabilize allopregnanolone signalling during the luteal phase, including:

1. Dutasteride, a 5-alpha reductase inhibitor

2. Isoallopregnanolone, a GABA-A modulating steroid antagonist

3. Ulipristal acetate, a selective progesterone receptor modulator

Implications of Therapeutic Advances

The review reflects on the implications of these therapeutic advances, including how they may promote our knowledge of affective regulation more generally. It concludes that these and other studies of PMDD may yield critical insight into the aetiopathogenesis of affective disorders, considering that:

1. Symptoms in PMDD have a predictable onset and offset, allowing for examination of affective state kinetics

2. GABAergic interventions in PMDD can be used to better understand the relationship between mood states, network regulation, and the balance between excitatory and inhibitory signalling in the brain

In summary, the interaction between allopregnanolone and the GABA system plays a significant role in reproductive-related mood disorders like PMDD.

Early clinical trials of compounds that stabilize allopregnanolone signalling during the luteal phase show promise, and these therapeutic advances may help improve our understanding of affective regulation and the etiopathogenesis of affective disorders. (Sikes-Keilp and Rubinow 2023).

Neuroactive steroids (NAS) allopregnanolone

NAS allopregnanolone (ALLO), is a positive allosteric modulator of the GABA A receptor (GABAA-R) involved in PMDD's pathophysiology.

Brexanolone, a synthetic version of allopregnanolone (ALLO), was FDA-approved for PPD in March 2019. PPD is believed to be related to NAS changes, with ALLO being a key player. Brexanolone has demonstrated rapid symptom relief in Phase II and Phase III clinical trials, reducing PPD symptoms within 60 hours of administration. This is a much faster response than selective serotonin reuptake inhibitors (SSRIs), which can take weeks to provide symptom relief.

Sepranolone, an ALLO isomer and GABA-A modulating steroid antagonist (GAMSA), is currently in Phase II clinical trials for PMDD. In an initial placebo-controlled trial, sepranolone reduced PMDD mood symptom scores by 75% when administered during the luteal phase in women with PMDD. Interestingly, sepranolone provided significant reduction in mood symptoms but not physical symptoms (such as breast tenderness, headaches, bloating) in PMDD (Hantsoo and Epperson 2020).

Another study used the 5α-reductase inhibitor dutasteride to treat PMDD and found that patients who received high doses (2.5 mg/day) of dutasteride experienced symptom improvement (Gao et al. 2023).

Natural products

Vitex agnus-castus

The study by Atmaca, Kumru, and Tezcan (2003) compared the efficacy of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), with that of Vitex agnus-castus extract in the treatment of premenstrual dysphoric disorder (PMDD) (Atmaca, Kumru, and Tezcan 2003).

The study included 41 patients with PMDD who were randomized to receive either fluoxetine or Vitex agnus-castus for two months. The outcome measures included the Penn daily symptom report (DSR), the Hamilton depression rating scale (HAM-D), and the clinical global impression-severity of illness (CGI-SI) and -improvement (CGI-I) scales (Atmaca, Kumru, and Tezcan 2003).

At the endpoint of the study, a similar percentage of patients responded to fluoxetine (68.4%, n = 13) and Vitex agnus-castus (57.9%, n = 11), with no statistically significant difference between the groups in terms of the rate of responders.

The study suggests that both fluoxetine and Vitex agnus-castus are effective in treating PMDD. However, fluoxetine was found to be more effective for psychological symptoms, while Vitex agnus-castus extract was more effective in diminishing physical symptoms (Atmaca, Kumru, and Tezcan 2003).

The systematic review by Cerqueira et al. (2017) aimed to evaluate the safety and effectiveness of Vitex agnus castus as a treatment for premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). The authors conducted a literature search using PubMed and Scielo databases, focusing on randomized controlled trials (RCTs) that compared Vitex agnus-castus with placebo or an active comparator in individuals with PMS or PMDD.

A total of eight RCTs were included in the study, with most of them focusing on PMS. The diagnostic criteria for PMS and PMDD changed over the years, and three different Vitex agnus-castus preparations were tested.

There was significant variability in the measurement of treatment outcomes between the studies, but all eight studies reported positive results for Vitex agnus-castus in the treatment of PMS or PMDD.

Vitex agnus-castus was overall well tolerated by the participants.

The main limitations of the review were the differences in the definition of diagnostic criteria, the instruments used as main outcome measures, and the various preparations of Vitex agnus-castus extracts, which limited the comparison of results between studies.

Despite these limitations, the authors concluded that the RCTs using Vitex agnus-castus for the treatment of PMS/PMDD suggested that Vitex agnus-castus extract is a safe and efficacious alternative to be considered for the treatment of PMS/PMDD symptoms (Cerqueira et al. 2017).

The systematic review and meta-analysis conducted by Verkaik et al. (2017) aimed to determine the efficacy, tolerability, and acceptability of Vitex agnus-castus preparations for the treatment of premenstrual syndrome (PMS). The study analysed 17 randomized controlled trials of Vitex agnus-castus in the treatment of PMS, with 14 of these being included in the quantitative analysis.

Thirteen out of the 14 studies reported positive effects of Vitex agnus-castus on total PMS symptoms when compared to placebo, dietary supplements, or herbal preparations. However, the authors noted that most of the trials were associated with a high risk of bias. The pooled effect of Vitex agnus-castus in placebo-controlled trials was large (Hedges g, -1.21; 95% confidence interval, -1.53 to -0.88), but the heterogeneity was extremely high (I(2), 91%). The study also found evidence of publication bias.

In conclusion, although the meta-analysis showed a large, pooled effect of Vitex agnus-castus in placebo-controlled trials, the high risk of bias, high heterogeneity, and risk of publication bias of the included studies prevent a definitive conclusion. The authors suggest that the pooled treatment effects should be viewed as explorative and, at best, overestimating the real treatment effect of Vitex agnus-castus for PMS symptoms. They emphasize the need for high-quality trials of appropriate size examining the effect of standardized extracts of Vitex agnus-castus in comparison to placebo, selective serotonin reuptake inhibitors, and oral contraceptives to establish relative efficacy (Verkaik et al. 2017).

The general recommendation is to start Vitex agnus-castus on day one of the menstrual cycle and continue to take it daily for as long as it is beneficial. Vitex agnus-castus can be taken long term if required. One indication that it needs to cease is if the cycle is becoming consistently longer.

Hypericum perforatum

A case report describes a case of PMDD who was initially treated with selective serotonin reuptake inhibitors. Due to intolerable gastrointestinal side effects with selective serotonin reuptake inhibitors, St. John's wort (900 mg/day) was substituted and much improvement in PMDD symptoms was noted for at least five-month follow-up. The authors propose that St. John's wort could be an alternative medication for PMDD, especially for patients experiencing intolerable side effects with selective serotonin reuptake inhibitors (Huang and Tsai 2003).

Another case report describes a patient with premenstrual dysphoric disorder (PMDD) requested treatment with St. John's Wort. She agreed to random assignment to either placebo or St. John's Wort for three months. She took placebo for the first month and St. John's Wort for the second month of her menstrual cycle. A rash developed within two weeks of treatment with St. John's Wort. The abstract does not mention the effect on the symptoms of PMDD (Sultana, Peindl, and Wisner 2000).

Concerns about drug-interactions

The compound in Hypericum perforatum responsible for drug interaction is hyperforin. Liquid extracts are generally very low in hyperforin and are unlikely to cause drug interactions related to drug metabolism. Some extracts such as Zeller Ze117 (Remotiv) is also low in hyperforin and it is not associated with drug interactions.

Saffron, Kava, Lavender and Zizyphus

Saffron is considered an alternative to Hypericum perforatum for depression.

Kava, ziziphus and many other herbs can be explored for their anxiolytic effects in PMDD.

Withania, Rhodiola, Eleuthero

Adaptogens can be considered for the fatigue and general sense of exhaustion and can be combined with anxiolytics, nervine tonics and other herbs for nervous tension, anxiety, stress and poor sleep.

Gut microbiome

The review "New insights on the impact of gut microbiota on premenstrual disorders. Will probiotics solve this mystery?" by O. A. Nabeh discusses the emerging evidence for the role of gut microbiota in premenstrual disorders (PMDs), which include premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) (Nabeh 2023).

These disorders are characterized by physical and psychological changes occurring in the luteal phase of the menstrual cycle. The direct secretory function of the microbiome and their integration in hormonal, neurotransmitters, and bioactive compounds secretion and activity support the speculation of microbiome’s role in PMDs (Nabeh 2023).

The review also highlights the bidirectional relationship between microbiome and steroid hormones and the impact of diet, drugs, and inflammation on both microbiome and PMDs incidence and severity. This justifies the need for more studies to determine the actual role of GM in PMDs and the possible potential of probiotics and prebiotics as therapeutic options.

Although there is no definitive answer yet on whether probiotics can solve the mystery of PMDs, the emerging evidence suggests that gut microbiome plays a role in these disorders, and probiotics and prebiotics may have potential as therapeutic options. Further research is needed to better understand the relationship between microbiome and PMDs and to determine the effectiveness of probiotics and prebiotics in treating these conditions (Nabeh 2023).

Kamishoyosan (Japanese Kampo medicine TJ-24)

The open-labelled pilot study conducted by K. Yamada and S. Kanba aimed to investigate the efficacy of kamishoyosan (TJ-24), a traditional Japanese herbal formula (kampo), as an alternative treatment for outpatients with premenstrual dysphoric disorder (PMDD). In this study, 30 patients with PMDD were treated with TJ-24 for six menstrual cycles.

The results showed that 19 patients (63.3%) experienced more than a 50% improvement in their total score on the Hamilton Depression Rating Scale (HAM-D) during the late luteal phase. Additionally, 14 patients (46.7%) went into remission, with their total HAM-D score dropping below 7. The study concluded that many patients with PMDD were successfully treated with TJ-24.

It is important to note that this was an open-labelled pilot study, which means that there was no control group or blinding. Therefore, further research, including randomized controlled trials, is needed to confirm the effectiveness of kamishoyosan for treating PMDD. However, the initial results from this study suggest that kamishoyosan may be a promising alternative treatment for PMDD (Yamada and Kanba 2007).

Kamishoyosan (TJ-24)

Daily dose: 2.5 g three times daily, orally.

Bupleurum falcatum 3 g
Paeonia lactiflora 3 g
Atractylodes lancea 3 g
Angelica sinensis 3 g
Poria cocus 2 g
Gardenia jasminoides 2 g
Eleutherococcus gracilistylus 1.5 g
Glycyrrhiza spp. 1.0 g
Zingiber officinalis 1.0 g
Mentha spp. 1.0 g
Phosphatidylserine (PS) and phosphatidic acid (PA) complex (PAS)

A clinical trial investigated the effects of a lecithin phosphatidylserine and phosphatidic acid complex (PAS) on premenstrual syndrome (PMS) symptoms. The study involved 40 women aged 18-45 years with a diagnosis of PMS, who were assigned to either take PAS (containing 400 mg PS & 400 mg PA per day) or a matching placebo. The primary outcome of the study was the PMS symptoms severity as assessed by using the Daily Record of Severity of Problems (DRSP).

The results found that PMS symptoms, as assessed by the DRSP Total score, improved significantly better (p = 0.001) over three cycles of PAS intake compared to the placebo. Additionally, women treated with PAS reported a greater improvement in physical (p = 0.002) and depressive symptoms (p = 0.068). They also reported a lower reduction of productivity (p = 0.052) and a stronger decrease in interference with relationships with others (p = 0.099) compared to the placebo group. No other DRSP scale or item showed significant results.

Regarding biomarkers, the salivary cortisol percentage increase of the cortisol awakening response (CAR) was significantly less pronounced in the follicular phase of cycle 4 than in the follicular phase of cycle 1 for subjects taking PAS when compared to subjects taking placebo (p = 0.018). Furthermore, the change of serum cortisol levels between visit 1 and visit 5 differed significantly between groups (p = 0.043). While serum cortisol levels of PAS treated females slightly decreased between visit 1 and visit 5, cortisol levels of females treated with placebo increased. For all other biomarkers, no treatment effects were observed over the 4 cycles study period.

In conclusion, the study substantiates the efficacy of PAS in reducing symptoms of PMS. The positive results of this clinical study merit consideration of developing the PAS complex as a potential for the treatment of PMDD (Schmidt et al. 2018).

N-acetylcysteine (NAC)

N-acetylcysteine (NAC) is an antioxidant and anti-inflammatory agent that has been studied for its potential benefits in various conditions, including PMDD (Rajabi, Haghanifar, and Tarrahi 2020). In a randomized clinical trial, NAC was found to be as effective as fluoxetine, a commonly prescribed medication for PMDD, in improving symptoms.

The study involved 119 childbearing females who were randomly divided into three groups: one group received 10 mg of fluoxetine twice daily, another group received 450 mg of NAC twice daily, and the third group received a placebo. The treatments were administered daily for two weeks within the initiation of the menstruation cycle for two menstruation cycles.

The results showed that all groups experienced significant improvements in their symptoms, with the NAC and fluoxetine groups showing greater improvements than the placebo group (Rajabi, Haghanifar, and Tarrahi 2020).

Magnesium

There is conflicting data regarding the presence of magnesium (Mg) deficiency and the therapeutic efficacy of Mg in premenstrual syndrome or premenstrual dysphoric disorder (PMDD). In a study, several blood measures of Mg and mood, were obtained before, immediately after, and the day following an intravenous Mg in women with (n = 17) and without (n = 14) prospectively diagnosed PMDD. The Mg infusion was showed to be associated with an improvement in mood.

Subsequently PMDD patients (n = 10) were randomized in a double-blind, placebo-controlled, crossover fashion. Patients (31.5%) and control subjects (27.5%) retained comparable mean percentages of Mg. Neither group differed in measures of mean Mg before, immediately after, or the day following Mg infusion.

Although there was a time effect for all mood measures in the patient group (p < .01 for all), there was neither a treatment nor time-by-treatment effect.

Contrary to prior reports, this study found no evidence of Mg deficiency in women with PMDD compared with control subjects. Furthermore, Mg was not superior to placebo in the mitigation of mood symptoms in women with PMDD (Khine et al. 2006).

Calcium

Alterations in calcium homeostasis have long been associated with many affective disorders. Cyclical fluctuations of the ovarian steroid hormones across the menstrual cycle influence calcium metabolism, affect intestinal calcium absorption and modulate 1,25-dihydroxyvitamin D synthesis. Evidence now suggests that abnormalities in calcium and vitamin D metabolism, specifically calcium and vitamin D deficiency, are responsible for these luteal-phase symptoms (Bocchieri and Thys-Jacobs 2008).

Plasma calcium level has been shown to be lower before menstruation, and a large trial found that 1,200 mg of elemental calcium as calcium carbonate daily alleviated tension, anxiety, fluid retention, pain, and food cravings in women with PMS.

Vitamin B6

A study aimed to compare the efficacy of a broad-spectrum micronutrient formula (mainly consisting of minerals and vitamins) to a single vitamin (B6) for the treatment of premenstrual syndrome (PMS). In this double-blind, randomised, treatment-controlled trial, 78 women with PMS were allocated to consume either micronutrients or vitamin B6 (80 mg/day) daily for three menstrual cycles. The primary outcome measure was the Daily Record of Severity of Problems (DRSP), which tracked changes in five PMS symptoms: psychological, somatic, total symptoms, impact ratings, and worst day ratings.

The results showed that both treatments produced comparable reductions in PMS symptoms with medium effect sizes (micronutrient ES = 0.50-0.56; B6 ES = 0.43-0.56). After three cycles, 72% of the micronutrient group and 60% of the vitamin B6 group were identified as being in full remission of PMS symptoms. The micronutrient-treated participants showed greater improvement in health-related quality of life than the B6 group (between-group d = 0.51, p < 0.05). For women who met the criteria for premenstrual dysphoric disorder (PMDD), the DRSP effect sizes were larger for those in the micronutrient condition (ES = 1.28-1.67) compared to those on B6 (ES = 0.50-0.75), although the group differences were not statistically reliable. No group differences in side effects or serious adverse effects were reported.

In conclusion, both treatments provided similar benefits for reducing PMS symptoms, with a greater effect of micronutrients on quality of life and potential clinical benefits for PMDD. However, as this is the first study to investigate these treatments for PMDD, systematic replication is required (Retallick-Brown, Blampied, and Rucklidge 2020).

References

Almaraz Trejo, Nancy Lizet, and José Ángel Castillo Marínez. 2023. 'Premenstrual dysphoric disorder and its psychological affectation in the workplace', Journal of Basic and Applied Psychology Research.

Atmaca, M., S. Kumru, and E. Tezcan. 2003. 'Fluoxetine versus Vitex agnus castus extract in the treatment of premenstrual dysphoric disorder', Hum Psychopharmacol , 18: 191-5.

Bocchieri, E., and S. Thys-Jacobs. 2008. 'Role of calcium metabolism in premenstrual syndrome', Expert Rev Endocrinol Metab, 3: 645-55.

Cerqueira, R. O., B. N. Frey, E. Leclerc, and E. Brietzke. 2017. 'Vitex agnus castus for premenstrual syndrome and premenstrual dysphoric disorder: a systematic review', Arch Womens Ment Health, 20: 713-19.

Gao, Q., W. Sun, Y. R. Wang, Z. F. Li, F. Zhao, X. W. Geng, K. Y. Xu, D. Chen, K. Liu, Y. Xing, W. Liu, and S. Wei. 2023. 'Role of allopregnanolone-mediated gamma-aminobutyric acid A receptor sensitivity in the pathogenesis of premenstrual dysphoric disorder: Toward precise targets for translational medicine and drug development', Front Psychiatry, 14: 1140796.

Griffin, L. D., and S. H. Mellon. 1999. 'Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes', Proc Natl Acad Sci U S A , 96: 13512-7.

Hantsoo, L., and C. N. Epperson. 2020. 'Allopregnanolone in premenstrual dysphoric disorder (PMDD): Evidence for dysregulated sensitivity to GABA-A receptor modulating neuroactive steroids across the menstrual cycle', Neurobiol Stress , 12: 100213.

Hapsari, Elsi Dwi, Yuria Mantani, and Hiroya Matsuo. 2006. 'The Prevalence of Premenstrual Dysphoric Disorder and Its Modulation by Lifestyle and Psychological Factors in High School Students', Bulletin of health sciences Kobe , 22: 19-28.

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